BACKGROUND: The deleterious impact of uranium on human health has been linked to its radioactive and heavy metal-chemical properties. Decades of research has defined the causal relationship between uranium mining/milling and onset of kidney and respiratory diseases 25 years later. OBJECTIVE: We investigated the hypothesis that uranium, similar to other heavy metals such as cadmium, acts like estrogen. METHODS: In several experiments, we exposed intact, ovariectomized, or pregnant mice to depleted uranium in drinking water [ranging from 0.5 microg/L (0.001 microM) to 28 mg/L (120 microM). RESULTS: Mice that drank uranium-containing water exhibited estrogenic responses including selective reduction of primary follicles, increased uterine weight, greater uterine luminal epithelial cell height, accelerated vaginal opening, and persistent presence of cornified vaginal cells. Coincident treatment with the antiestrogen ICI 182,780 blocked these responses to uranium or the synthetic estrogen diethylstilbestrol. In addition, mouse dams that drank uranium-containing water delivered grossly normal pups, but they had significantly fewer primordial follicles than pups whose dams drank control tap water. CONCLUSIONS: Because of the decades of uranium mining/milling in the Colorado plateau in the Four Corners region of the American Southwest, the uranium concentration and the route of exposure used in these studies are environmentally relevant. Our data support the conclusion that uranium is an endocrine-disrupting chemical and populations exposed to environmental uranium should be followed for increased risk of fertility problems and reproductive cancers.